Choline is an essential nutrient, and eating a choline deficient diet results in hepatosteatosis and liver and muscle damage in humans and rodents (Buchman et al., 1995; Zeisel, 2005; Zeisel et al., 1991). In rodents, choline in maternal diet during pregnancy is important for normal fetal brain development (Albright et al., 1999a; Albright et al., 1999b; Craciunescu et al., 2003; Jones et al., 1999; Niculescu et al., 2006). Choline has three possible metabolic fates: it can be acetylated to form acetylcholine, an important neurotransmitter; it can be phosphorylated and then used as a constituent of membranes; and it can be oxidized to form betaine and then used as a methyl donor (Zeisel, 2006). Choline dehydrogenase (CHDH, EC 1.1.99.1), an inner mitochondrial membrane protein, is the enzyme responsible for catalyzing the first of two reactions leading to the production of betaine through the oxidation of dietary choline (Chi-Shui and Ru-Dan, 1986; de Ridder and van Dam, 1973; Haubrich and Gerber, 1981; Huang and Lin, 2003; Mann and Guastel, 1937; Rendina and Singer, 1959). It is through betaine that choline contributes to the pool of methyl groups available for DNA and protein methylation (Olthof and Verhoef, 2005). CHDH is primarily expressed in liver and kidney, with humans having the highest expression levels in kidney.
CHDH activity can influence tissue choline metabolite concentrations because the oxidation of choline is irreversible, committing the choline moiety to the methyl donation pathway (Zeisel 2005). Choline that is not used to form betaine can be acetylated to form acetylcholine, or phosphorylated to form phosphatidylcholine and sphingomyelin (Zeisel 2006). CHDH activity can influence tissue homocysteine concentrations because betaine donates a methyl group to homocysteine (tHcy), catalyzed by betaine:homocysteine methyl transferase (BHMT, EC 2.1.1.5). The product of this reaction is methionine which is the precursor for S-adenosylmethionine (SAM), the most important methyl donor in biochemical reactions (including DNA and protein methylations). Dietary betaine supplementation is effective in lowering plasma tHcy concentrations in humans (Olthof and Verhoef 2005); elevated plasma tHcy concentration is associated with increased risk of cardiovascular disease (Glueck, Shaw et al. 1995; Melenovsky, Stulc et al. 2003).
Some humans are more susceptible to developing organ dysfunction when fed a choline deficient diet because they have one of several single nucleotide polymorphisms (SNPs) in genes related to choline metabolism (da Costa et al., 2006). One such functionally important SNP, rs12676, is located in the coding region of the CHDH gene (da Costa et al., 2006). This is a common SNP, with 42% of the Chapel Hill, N.C., United States of America, population having at least one allele (da Costa et al., 2006). It has been reported that 83% of pre-menopausal women heterozygous for the rs12676 allele developed organ dysfunction when fed a choline deficient diet compared to only 20% of women with a wildtype genotype (da Costa et al., 2006).
In addition, it has been reported that dietary choline deficiency can alter reproductive performance in chickens and boar (Einarsson and Gustafsson, 1973; Ferguson et al., 1975). Sperm motility depends on normal mitochondrial function (Kasai T, et al., 2002). Mitochondrial membranes must maintain an electrochemical gradient in order for oxidative phosphorylation and ATP generation to proceed. According to the 2002 National Survey of Family Growth, approximately 2.1 million couples per year in the United States seek help in dealing with infertility. Of these couples, roughly 30% of the infertility can be attributed to male factor infertility. Asthenospermia, the condition of having low sperm motility, is present in 15%-17% (Maconochie et al., 2004; Thonneau et al., 1991) of these men and, in many cases, the cause is unknown.
The presently disclosed subject matter describes methods of screening for and treating low sperm motility in male subjects as a result of a defect in one or more choline metabolism genes. In another aspect, the presently disclosed subject matter describes methods of screening for and treating subjects having impaired mitochondrial function as a result of a defect in one or more choline metabolism genes.